In order to prepare solid, shaped dosage forms from fine particles or powders, it is generally necessary to process the powders in a manner to improve their flowability, cohesiveness and other characteristics which will enable the resulting material to be fabricated by conventional processes such as tableting, encapsulation, molding, etc. into a satisfactory unit form that can suitably deliver an agent into the environment of use.
Various processes are well-known in the pharmaceutical art for modifying starting powders or other particulate materials, in which typically the powders are gathered together with a binder material into larger permanent free-flowing agglomerates or granules referred to collectively as a "granulation."
For example, solvent-assisted "wet" granulation processes are generally characterized in that the powders are combined with a binder material and moistened with water or an organic solvent under conditions to result in formation of a wet granulated mass from which the solvent must then be evaporated. Such processes while widely employed have certain recognized limitations arising from the use when necessary of nonaqueous solvents which are environmentally deleterious, and furthermore may not be readily adaptable in connection with moisture sensitive medicaments.
In particular, formulations comprising hydrophilic cellulose ether polymers as a carrier base or matrix material, can present problems in formulation by aqueous wet granulation means. Alternative "dry granulation" processes, which often depend on fairly complicated milling schemes to produce a suitable granulation, also have acknowledged disadvantages in relation to such formulations. Nor are the finely divided cellulose ether particles in higher concentrations readily suitable in a direct compression process.
Such cellulose ether-based formulations, as exemplified in U.S. Pat. Nos. 3,065,143, 3,870,790, 4,226,849, 4,357,469, 4,389,393, 4,540,566, 4,795,327 and 4,849,229 (all assigned to Forest Laboratories, Inc.), have been found useful in particular to prepare sustained release dosage forms.
In such dosage forms the hydrophilic cellulose ether polymer typically functions as a binder or matrix system to regulate release of components of the dosage form. When introduced into the environment, the polymer partially hydrates where directly exposed to water to form a gelatinous layer. This original protective gel layer, once formed, permits additional fluid to penetrate into the interior of the dosage device. As the outer gel layer begins to fully hydrate and dissolve, a new layer replaces it which optimally is sufficiently strong to continue to retard outward diffusion and thus maintain the sustained release features of the dosage form, for the desired length of time.
The art has long recognized the benefits of achieving a long-lasting and regular incremental release of a therapeutic agent upon administration, and accordingly it has been a continuing objective to provide improved compositions and processes for preparing such cellulose ether-based sustained release dosage forms.
Certain melt granulation techniques have been developed in the art which in general comprise the use of room temperature solid or semi-solid materials having a relatively low softening or melting range to promote granulation of powdered or other materials, in the substantial absence of added water or other liquid solvents. The low melting solids, when heated to a temperature at or near or the melting range, liquify to act as a binder or granulating medium which spreads itself over the surface of powdered or particulate materials with which it is associated, and on cooling, forms a solid granulated mass in which the powder or particulate starting materials are bound. The resulting melt granulation can then be provided to a tablet press, mold, or encapsulator, etc., for preparing the dosage form, see, e.g., Pharmaceutical Dosage Forms: Tablets, Vol. 1 (2d Ed.) ed. by Lieberman et al., Marcel Dekker Inc. (1989), pp. 148-151.
It will be evident that a melt granulation process, by dispensing with wetting and drying steps, as well as facilitating a virtually "one-pot" granulating technique, can potentially provide significant improvements over other granulation methods, and that such a process and compositions, where these can be applied, would be highly useful to the art.
It has now been discovered and is an aspect of this invention that hydrophilic cellulose ether-based compositions, particularly high concentration cellulose compositions (e.g. 20 wt. % or higher) may be prepared by a melt granulation process.
The compositions may be conveniently tableted or otherwise manufactured into shaped dosage forms comprising a therapeutic agent, especially sustained release dosage forms.